title: Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7.
abstract: Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA. ingrid@gene.com
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Wertz
authors.forename: Saritha
authors.initials: S
authors.lastname: Kusam
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lam
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.forename: Wendy
authors.initials: W
authors.lastname: Sandoval
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Helgason
authors.forename: James A
authors.initials: JA
authors.lastname: Ernst
authors.forename: Mike
authors.initials: M
authors.lastname: Eby
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
authors.forename: Josh S
authors.initials: JS
authors.lastname: Kaminker
authors.forename: Karen M
authors.initials: KM
authors.lastname: O'Rourke
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chiu
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Ludlam
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Leong
authors.forename: Erin C
authors.initials: EC
authors.lastname: Dueber
authors.forename: Heather
authors.initials: H
authors.lastname: Maecker
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017239:Paclitaxel / Q000494:pharmacology; D010597:Pharmacogenetics; D010766:Phosphorylation / Q000187:drug effects; D011123:Polyploidy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014404:Tubulin; D050257:Tubulin Modulators; D014750:Vincristine; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel